Role of WNT Pathway Mutations within Oligometastatic Castration-Sensitive Prostate Cancer

Purpose/Objective(s)WNT signaling is a cellular pathway that has been implicated in the development and progression of prostate cancer. Within castration-resistant prostate cancer (CRPC), WNT pathway alterations have been observed in up to 20% of patients and are associated with worse progression-free and overall survival. Within castration-sensitive prostate cancer (CSPC), the consequence of WNT alterations is unknown. Oligometastatic CSPC (omCSPC) represents a unique disease state in which metastasis directed therapy (MDT) has demonstrated improvements in progression-free and androgen deprivation therapy (ADT)-free survival. Herein, we investigate the role of genomic alterations within the WNT pathway in men with omCSPC.Materials/MethodsWe performed an international multi-institutional retrospective study of 277 men with metachronous omCSPC (≤5 metastases on conventional imaging) who underwent targeted sequencing. Patients were classified by presence of pathogenic somatic WNT mutations including APC, RNF43, and CTNNB1. Kaplan-Meier survival curves were generated for radiographic progression-free survival (rPFS) and overall survival (OS), stratified according to WNT mutation status and treatment, and then compared with the log-rank test. Pearson's χ2, Mann-Whitney U, and independent t-test were used to determine differences in clinical factors between treatment/genomic groupings.ResultsA pathogenic WNT mutation was detected in 11.2% (5.4% APC, 4.7% CTNNB1, 2.9% RNF43) of patients. Patients with WNT mutations were less likely to present with pelvic lymph node metastases (29.0% vs 50.4%; p=0.02) but more likely to have lung metastases (16.1% vs 1.6%; p<0.01). At time of oligometastasis, these patients were treated with MDT alone (33.9%), MDT + limited course of systemic therapy (20.6%), systemic therapy alone (22.4%), or observation (defined as no treatment for ≥6 months following diagnosis). Patients who received systemic therapy alone were found to have higher PSA at time of oligometastasis (18.8 vs 7.2, p<0.01) but otherwise had no differences in Gleason score or number/location of metastases compared to those that received MDT. Within the entire cohort, log-rank testing demonstrated WNT mutations were associated with significantly worse OS (p=0.01) but not rPFS (p=0.97). Among patients treated with systemic therapy alone, WNT was associated with significantly worse 3-yr rPFS (12% vs 64%; p<0.01) and OS (3-yr OS 69% vs 98%; p=0.01). In patients treated with MDT +/- systemic therapy, no difference was observed in either 3-yr rPFS (59% vs 34%, p=0.26) or 3-yr OS (100% vs 98%; p=0.60).ConclusionWNT pathway mutations are associated with a worse OS in men with omCSPC that appears to be most pronounced in patients receiving systemic therapy alone. Given these findings, MDT may hold an important role in the initial management of WNT-mutated omCSPC.